Date of Award

5-2023

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biomedical and Chemical Engineering and Sciences

First Advisor

Vipuil Kishore

Second Advisor

Kenia P. Nunes

Third Advisor

Venkat Keshav Chivukula

Fourth Advisor

Manolis Tomadakis

Abstract

Astrocytes are crucial in preserving the structural and functional integrity of the central nervous system (CNS). They participate in several physiological processes, such as the uptake of neurotransmitters, control of extracellular ion concentration, and preservation of the blood-brain barrier. Recent research has raised the possibility that astrocytes are also involved in the onset and development of Alzheimer's disease (AD). While the precise mechanisms underlying the development and progression of AD are not fully understood, recent research has suggested that age-related changes in the brain extracellular matrix (ECM) properties may play a critical role in the progression of the disease. Investigating the impact of brain ECM properties on astrocyte cell response can help unravel the possible impact of the ECM on AD. In this study, in vitro xeno-free biomimetic hydrogel-based brain ECM models were employed to investigate the impact of ECM composition and stiffness on astrocyte cell response. Variable ratios of human collagen type I and thiolated hyaluronic acid (HA) crosslinked with polyethylene glycol diacrylate were used to create the xeno-free ECM models. Results demonstrated that modifying the composition of the ECM produced hydrogels with varied stiffness that were comparable to the stiffness of the native brain ECM. Hydrogels rich in collagen showed better stability and increased swelling. Hydrogels with lower HA composition showed better cell spreading and metabolic activity. In addition, softer hydrogels showed greater cell spreading, elevated GFAP expression, and decreased ALDH1L1 expression, suggesting that matrix stiffness influences astrocyte activation. This study proposes a basic model of the brain ECM to study the synergistic effects of ECM composition and stiffness on astrocytes. Future studies can focus on building on this work by incorporating additional matrix proteins to identify key ECM biomarkers and develop new strategies to overcome the impact of ECM changes on the onset and progression of neurodegenerative illnesses such as AD.

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